Central obesity, insulin resistance and diabetes have emerged as public health issues of considerable importance due to the magnitude of the problem and the associated high risk of atherosclerotic cardiovascular disease. The planned renewal of our Program Project will utilize the latest cellular and molecular approaches to explore the mechanisms and new therapeutic opportunities for atherosclerotic cardiovascular disease associated with diabetes and the metabolic syndrome. The multidisciplinary team from the current version of the PPG will remain intact in the renewal. The team will be further strengthened by addition of new collaborators and key consultants. We have developed new innovative techniques and novel rodent and translational swine models to address the important issues of mechanisms leading to atherosclerosis in diabetes and the metabolic syndrome. The overall unifying theme is that components of the metabolic syndrome and diabetes lead to accelerated rates of atherosclerosis and vascular injury responses due to activation of key growth and inflammatory signals in the vascular wall and infiltrating immune cells. These factors further induce migration and activation of key cellular components into adipose tissue and the vascular wall. The Program will have 5 highly integrated projects and 3 Cores (mouse/histology, Swine Core and Administrative Core).Project 1: Will utilize new mouse and swine models of insulin resistance and diabetes to test the hypothesis that oxidized lipids including those generated by 12/15-lipoxygenase (12/15-LO) play a role in vascular disease and inflammation by activation of particular cytokines and downstream signals in adipocytes and monocyte/macrophages. The link between activation of components of the innate immune system and development of the chronic inflammation leading to atherosclerosis will be studied. Project 2: Will test the hypothesis that chronic hyperglycemia in diabetes decreases macrophage ABCG1 function and results in increased macrophage foam cell formation in vivo. We hypothesize that the reduction in macrophage ABCG1 function increases atherosclerosis in the setting of diabetes. ABCG1 is a novel ABC transporter that is present on macrophages and is a primary regulator of cholesterol efflux from macrophages to HDL in reverse cholesterol transport. Project 3: Will explore the important role of vascular smooth muscle cell (VSMC) growth given the importance of this in restenosis following vascular injury in insulin resistant and diabetic states. Specifically the role of the helix-loop-helix transcription factor Id3 will be tested using in vitro and in vivo approaches. Id3 is a major factor leading to VSMC growth and its expression is increased in states of insulin resistance and by 12-LO. Project 4: Will explore the important hypothesis that lymphocyte trafficking into and out of the walls of large arteries is altered in insulin resistant states and diabetes and that this process contributes to accelerated atherosclerosis. The project will explore why and how atherosclerosis results in chronic inflammation of the vascular wall and how insulin resistance and diabetes modified this process. Project 5: Will test the hypothesis that diabetes and insulin resistance lead to key changes in VSMC and monocytes associated with atherosclerosis. This is a consequence of increased activity/expression of enzymes such as 12/15-LO that form proatherogenic oxidized lipids and augmented expression of inflammatory cytokines/chemokines in VSMC. These events lead to VSMC migration, increased subendothelial VSMC-monocyte interactions and foam cell formation. All projects will rely on use of the mouse/histology and swine cores for these integrated studies in the PPG.